PGC-1?/ERR? Regulate The EMT Process To Promote Invasion And Metastasis In Endometrial Cancer

Objective:To analysis of the relationship between PGC-1?,ERR?and the risk of advanced myometrial invasion in endometrial carcinoma,then to investigated the role of PGC-1?and ERR?in endometrial cancer?EC?and whether they regulate the epithelial-mesenchymal-transition?EMT?therefore invasion and metastasis.Methods:A total of 81 cases of endometrial cancer tissues and 40 cases of normal endometrial tissues confirmed by surgical pathology were collected from September2011 to September 2017 in the Department of Gynecology,Fujian Maternal and Child Health Hospital.PGC-1?and ERR?protein expression in a tissue microarray including81 cases endometrial carcinoma and 40 cases normal endometrium specimens were analyzed by immunohistochemistry.Real-time qPCR and Western blotting were used to detect the expression of PGC-1?,ERR?mRNA and protein in human endometrial cancer cell lines RL952,ECC-1,HEC-1A and HEC-1B cells in vitro.To regulate the expression of PGC-1?and ERR?,silencing of PGC-1?by lentivirus-mediated RNA interference,or the lentiviral vector over-expressing the ERR?gene was transiently transfected into EC cells.ECC-1 and HEC-1A cells were treated with XCT790 which specifically down-regulated ERR?expression.Before and after the regulation of PGC-1?and ERR?expression,the expression of E-cadherin and Vimentin protein was detected by cellular immunofluorescence technique and Western blot.The cell scratch test and transmembrane cell assay were used to observe the changes of invasion and migration ability.Results:1.Compared with the clinical characteristics of the endometrial cancer?case group?and normal endometrial tissue?control group?.Age,body mass index,blood glucose,triglyceride and plasma osmotic pressure in patients with endometrial cancer were higher than those of the control group?P<0.05?.the expression levels of PGC-1?and ERR?in endometrial cancer were significantly increased,the difference was statistically significant?P<0.05?.2.The expression of PGC-1?and ERR?in different myometrial infiltration groups was statistically different(P_PGC-1?=0.038 and P_ERR?=0.039,respectively).PGC-1?and ERR?are risk factors for myometrial invasion in patients with endometrial cancer(OR_PGC-1?=4.75,95%CI 1.056-21.36;OR_ERR?=2.579,95%CI 1.025-6.49).However,there was no correlation between PGC-1?or ERR?expression and FIGO stage,tumor histological grade,and lymph node metastasis.3.PGC-1?expression was silenced by PGC-1?-siRNA in ECC-1 cells,the expression of PGC-1?mRNA in the PGC-1?-siRNA group was significantly lower than that in the BLANK group?inhibition rate was 89.5%?.The level of ERR?mRNA in siPGC-1?cells was also decreased.In the HEC-1A cells,the ERR?mRNA level in OV-ERR?group was significantly higher than that in the BLANK and CON groups?the expression increased by 188%?.With the upregulation of ERR?,the expression of PGC-1?mRNA increased by 131%.PGC-1?and ERR?proteins was consistent with mRNA expression in HEC-1A cell.4.Targeted inhibition of PGC-1?resulted in decrease the migration distance?F=200.980,P<0.001?and the number of transmembrane cells?F=847.642,P<0.001?in ECC-1 cells after the decrease in PGC-1?/ERR?expression.Overexpression of PGC-1?/ERR?increased the migration distance in HEC-1A cells?F=152.652,P<0.001?,and the number of transmembrane cells increased significantly?F=198.471,P<0.001?.Correlation analysis showed that the expression levels of PGC-1?and ERR?mRNA were positively correlated with migration distance?rPGC-1?=0.979;rERR?=0.995?,and positively correlated with the number of transmembrane cells?rPGC-1?=0.984;rERR?=0.974?.5.The protein expression of E-Cadherin was increased in ECC-1 cells after inhibition of PGC-1?and ERR?expression?F=2021.448,P<0.001?,while the protein expression of Vimentin was decreased?F=5533.24,P<0.001?.In contrast,overexpression of ERR?in HEC-1A cells increased expression of PGC-1?and ERR?,resulting decreased relative expression of E-Cadherin protein?F=3087.854,P<0.001?,and increased relative expression of Vimentin protein?F=2992.792,P<0.001?.Conclusion:1.PGC-1?and ERR?are poor prognostic indicators of endometrial cancer,which are risk factors for invasive endometrial cancer.it is expected that ERR?/PGC-1?expression level regard as a biomarker for predicting the prognosis of endometrial cancer.2.The expression levels of PGC-1?and ERR?are closely related to the invasion and migration of endometrial cancer cells.The expression of PGC-1?and ERR?is regulated by the involvement of EMT phenotype in endometrial cancer cells.Targeted inhibition of PGC-1?/ERR?is expected to be a new therapeutic strategy for invasion and metastasis of endometrial cancer.